The immunopathological landscape of human pre-TCRα deficiency: From rare to common variants

Area of Science:

• Immunology
• Human Genetics

Background:

• The pre-T cell receptor alpha (pre-TCRα) chain is crucial for T cell development.
• Genetic variations in the PTCRA gene can affect pre-TCRα expression and T cell homeostasis.

Purpose of the Study:

• To investigate the impact of rare biallelic loss-of-function PTCRA variants on T cell populations and clinical outcomes.
• To characterize the immunological and clinical phenotype associated with a common hypomorphic PTCRA variant in specific populations.

Main Methods:

• Analysis of circulating T cell counts (naive αβ, memory αβ, γδ T cells) in individuals with PTCRA variants.
• Assessment of TCRα repertoire bias.
• Clinical evaluation for infections, lymphoproliferation, and autoimmunity.

Main Results:

• Biallelic loss-of-function PTCRA variants result in low naive αβ T cell counts, biased TCRα repertoire, and increased susceptibility to infections and autoimmunity in a minority of cases.
• Homozygosity for a common hypomorphic PTCRA variant is associated with normal naive αβ T cell counts but elevated γδ T cell counts and increased frequency of autoimmune conditions.

Conclusions:

• Noncanonical thymic differentiation pathways can partially compensate for impaired pre-TCRα expression, allowing for some αβ T cell development.
• Even residual pre-TCRα expression can influence T cell differentiation and predispose individuals to autoimmune diseases.